Comprehensive characterization of genetic aberrations underlying human cancer is essential for improving tumor diagnostics, identifying therapeutic targets, developing rational combination therapies and optimizing clinical trial designs3. Large scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, continue to reveal an increasingly detailed picture of the genetic aberrations in many cancer types, but focus largely on characterizing genetic aberrations in the coding regions of DNA2-5. However, in a significant proportion of tumors, the number of detectable genetic aberrations in driver oncogenes is too low to explain malignant transformation6. This is exemplified by a recent study, in which ˜15% of lung adenocarcinoma lacked gene mutations affecting any of the hallmarks of cancer7,8. These observations suggest that mechanisms other than genetic aberrations may be involved in malignant transformation.